rs1057079

Variant names:

• chr1-11145001-C-T
• rs1057079
• NM_004958.4:c.4731G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004958.4(MTOR):​c.4731G>A​(p.Ala1577Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,613,390 control chromosomes in the GnomAD database, including 413,347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1577A) has been classified as Uncertain significance. The gene MTOR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.56 (29032 hom., cov: 31)
  • Exomes 𝑓: 0.72 (384315 hom.)
• Consequence: MTOR NM_004958.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.869
• Publications: 93 publications found

Genes affected

MTOR (HGNC:3942): (mechanistic target of rapamycin kinase) The protein encoded by this gene belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stresses such as DNA damage and nutrient deprivation. This kinase is a component of two distinct complexes, mTORC1, which controls protein synthesis, cell growth and proliferation, and mTORC2, which is a regulator of the actin cytoskeleton, and promotes cell survival and cell cycle progression. This protein acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. Inhibitors of mTOR are used in organ transplants as immunosuppressants, and are being evaluated for their therapeutic potential in SARS-CoV-2 infections. Mutations in this gene are associated with Smith-Kingsmore syndrome and somatic focal cortical dysplasia type II. The ANGPTL7 gene is located in an intron of this gene. [provided by RefSeq, Aug 2020]

MTOR-AS1 (HGNC:40242): (MTOR antisense RNA 1)

ACMG classification

Specifications for MTOR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 1-11145001-C-T is Benign according to our data. Variant chr1-11145001-C-T is described in ClinVar as Benign. ClinVar VariationId is 516654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.869 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004958.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTOR	NM_004958.4	MANE Select	c.4731G>A	p.Ala1577Ala	synonymous	Exon 33 of 58	NP_004949.1	P42345
	MTOR	NM_001386500.1		c.4731G>A	p.Ala1577Ala	synonymous	Exon 33 of 58	NP_001373429.1	P42345
	MTOR	NM_001386501.1		c.3483G>A	p.Ala1161Ala	synonymous	Exon 32 of 57	NP_001373430.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTOR	ENST00000361445.9	TSL:1 MANE Select	c.4731G>A	p.Ala1577Ala	synonymous	Exon 33 of 58	ENSP00000354558.4	P42345
	MTOR	ENST00000934315.1		c.4785G>A	p.Ala1595Ala	synonymous	Exon 33 of 58	ENSP00000604374.1
	MTOR	ENST00000934312.1		c.4752G>A	p.Ala1584Ala	synonymous	Exon 33 of 58	ENSP00000604371.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85698 AN: 151880 Hom.: 29024 Cov.: 31

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.783

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.688

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.609

GnomAD2 exomes AF: 0.686 AC: 172411 AN: 251352 AF XY: 0.692

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.728

Gnomad ASJ exome AF: 0.581

Gnomad EAS exome AF: 0.813

Gnomad FIN exome AF: 0.721

Gnomad NFE exome AF: 0.741

Gnomad OTH exome AF: 0.690

GnomAD4 exome AF: 0.718 AC: 1049597 AN: 1461392 Hom.: 384315 Cov.: 51 AF XY: 0.717 AC XY: 521497 AN XY: 727030

African (AFR) AF: 0.134 AC: 4483 AN: 33474

American (AMR) AF: 0.718 AC: 32104 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 15201 AN: 26128

East Asian (EAS) AF: 0.835 AC: 33148 AN: 39696

South Asian (SAS) AF: 0.654 AC: 56439 AN: 86248

European-Finnish (FIN) AF: 0.721 AC: 38482 AN: 53410

Middle Eastern (MID) AF: 0.684 AC: 3943 AN: 5768

European-Non Finnish (NFE) AF: 0.742 AC: 824572 AN: 1111576

Other (OTH) AF: 0.683 AC: 41225 AN: 60382

GnomAD4 genome AF: 0.564 AC: 85707 AN: 151998 Hom.: 29032 Cov.: 31 AF XY: 0.567 AC XY: 42106 AN XY: 74304

African (AFR) AF: 0.159 AC: 6585 AN: 41428

American (AMR) AF: 0.654 AC: 9985 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.593 AC: 2057 AN: 3466

East Asian (EAS) AF: 0.804 AC: 4158 AN: 5174

South Asian (SAS) AF: 0.640 AC: 3082 AN: 4816

European-Finnish (FIN) AF: 0.720 AC: 7599 AN: 10560

Middle Eastern (MID) AF: 0.695 AC: 203 AN: 292

European-Non Finnish (NFE) AF: 0.736 AC: 50032 AN: 67968

Other (OTH) AF: 0.611 AC: 1292 AN: 2114

Alfa AF: 0.651 Hom.: 80188

Bravo AF: 0.544

Asia WGS AF: 0.683 AC: 2376 AN: 3478

EpiCase AF: 0.732

EpiControl AF: 0.734

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	1.6
DANN	Benign	0.85
PhyloP100		0.87
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057079; hg19: chr1-11205058; COSMIC: COSV63875443;